Is KL p.Val331Ile (c.991G>A) pathogenic?

KL p.Val331Ile (c.991G>A) is classified Conflicting classifications of pathogenicity in KL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.0538); Very rare (popmax 0.00988%, sas).

How common is KL p.Val331Ile (c.991G>A) in the general population?

KL p.Val331Ile (c.991G>A) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about KL p.Val331Ile (c.991G>A)?

AlphaMissense predicts likely benign (score 0.0538) — an in-silico prediction, not a clinical call.

KL p.Val331Ile

c.991G>A · rs370772575 · VCV2715648

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0538	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -1.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.066	GERP -1.8, phastCons 0.013
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	6.532	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,080 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.00186% 30/1,613,922 alleles · very rare exomes 24/1,461,794 · genomes 6/152,128 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,120
Admixed American	0.00667%	14,997
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00223%	44,904
African / African-American	0.00133%	74,914
European (non-Finnish)	0.000932%	107,267

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: KL
Protein: p.Val331Ile
Coding: c.991G>A
MANE Select: NM_004795
dbSNP: rs370772575
Type: single nucleotide variant
Location: chr13:33053938 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 331: an α-helix; the 'glycosyl hydrolase-1 1' region

Full KL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KL p.Val331= Likely benign ★ same residue
KL c.1331-3C>A Uncertain significance ★★ same type
KL p.Ala3Thr Uncertain significance ★★ ⚠ same type
KL p.Ala50Val Uncertain significance ★★ ⚠ same type
KL p.Ala656Thr Uncertain significance ★★ ⚠ same type
KL p.Ala663Thr Uncertain significance ★★ ⚠ same type
KL p.Ala987Thr Uncertain significance ★★ ⚠ same type
KL p.Arg179Trp Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/kl-p-val331ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown